Theophylline or 1,3-dimethylxanthine is well known as a useful vasodilator and has been used as a bronchodilator. Unfortunately, the use of this agent has been restricted because of adverse reactions in aminophylline hypersensitive patients. It has also been known to incapacitate patients to whom it is administered because of gastrointestinal side effects. Dihydroxy propyl theophylline or dyphylline is of pharmacological interest because of its relative lack of toxicity and relative freedom from the side effect of theophylline itself. Unfortunately, however it is known that dyphylline is extremely rapidly passed through the human system and 83% of an administered dose has been found to be excreted, unchanged in the urine (Simons K.J., Simons F.E.R,. J. Pharm. Sci., 1979; 68:1327-28.)
While dyphylline has been marketed as a bronchodilator this extremely rapid, substantially non metabolizing, elimination has severly restricted the use of this very valuable agent.
The metabolization of theophylline itself is quite different. Examination of the urine samples of persons to whom theophylline has been administered show virtually complete metabolization of this agent (Monks T.J., Caldwell J., Smith R.L. Clin. Pharmacal. Ther., 1979; 26:513-24.)
Probenecid is a uricosuric and renal tubular blocking agent. It has been reported to inhibit the renal transport of various types of pharmacologically active compounds (see PDR 33rd Edition, 1979 pages 1114-1142). The prime purpose of probenecid is in gout therapy for enhancing the elimination of uric acid. Theophylline as well as being a broncho and vasodilator has useful diuretic properties. Certain studies were performed (Matheson L.E., Jr., Brighley L., Hendles L. Am. J. Hosp. Pharm., 1977; 34:496-99.) to determine the blood serum levels of patients to whom theophylline and probenecid had been administered. It will be understood that in gout patients administration of a diuretic together with administration of an agent, such as probenecid, which increases the urinary excretion of uric acid would be considered as a desirable form of therapy. These studies were carried out utilizing techniques which, it was later found, gave falsely high readings of theophylline concentration in the presence of benemid. Since, as stated heretofore theophylline is substantially completely metabolized there was no intention of enhancing the retention of theophylline in the system by co-administration of probenecid.